Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Mohammed F. Alosaimi, Manfred Hoenig, F. Jaber, Craig D. Platt, Jennifer Jones, Jacqueline Wallace, Klaus Michael Debatin, Ansgar Schulz, Eva Jacobsen, P. Möller, Hanan E. Shamseldin, Ferdous Abdulwahab, N. Ibrahim, H. Alardati, Faisal Almuhizi, Ibraheem F. Abosoudah, Talal A. Basha, J. Chou, Fowzan S. Alkuraya, Raif S. Geha

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Background: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. Objective: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. Methods: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. Results: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. Conclusion: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

Original languageEnglish
Pages (from-to)574-583.e5
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2019
Externally publishedYes


  • 4-1BB
  • CD137
  • EBV
  • Hodgkin lymphoma
  • immunodeficiency


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